The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK is the synthesis and evaluation of potential treatment medications for cocaine addiction. The strong association of high risk behaviors related to the spread of HIV with cocaine addiction makes the effort to develop cocaine treatment medications highly related to the fight against AIDS. In this fiscal year we continued the effort to develop analogs of GBR12909 as putative cocaine antagonists or cocaine substitution- type medications. Previous studies in Rhesus monkeys showed that daily administration of GBR12909 and a long-acting ester derivative of GBR12909 1-[2-[Bis(4-fluorophenyl)methoxy[ethyl]-4- (3-hydroxy-3-phenylpropyl)piperaziny] decanoate suppresses cocaine self-administration without the development of tolerance. A single administration of this agent almost eliminated cocaine self-administration in Rhesus monkeys for one month. Other efforts demonstrated that the clinically available dopamine releaser, phentermine, decreased cocaine self-administration in Rhesus monkeys. A particularly important study demonstrated that administration of medications which increase both synaptic DA and 5-HT have no abuse liability yet decrease cocaine self- administration. Other efforts involve antagonists of the serotonin 4 receptor (5-HT4) as potential treatments of cocaine- induced cardiac arrhythmia. An important study demonstrated that a high affinity ligand for all three biogenic amine transporters blocks the ability of methamphetamine to release DA, 5-HT and NE. Clinical and laboratory experiments continued to demonstrate robust changes in the serotonergic systems during cocaine withdrawal. These results support the hypothesis that cocaine withdrawal is associated with a dual deficit of dopamine and serotonin and provide a strong rationale for the treatment of cocaine addiction with medications which affect both neurotransmitters.